title: Intrinsic-mediated caspase activation is essential for cardiomyocyte hypertrophy.
abstract: Cardiomyocyte hypertrophy is the cellular response that mediates pathologic enlargement of the heart. This maladaptation is also characterized by cell behaviors that are typically associated with apoptosis, including cytoskeletal reorganization and disassembly, altered nuclear morphology, and enhanced protein synthesis/translation. Here, we investigated the requirement of apoptotic caspase pathways in mediating cardiomyocyte hypertrophy. Cardiomyocytes treated with hypertrophy agonists displayed rapid and transient activation of the intrinsic-mediated cell death pathway, characterized by elevated levels of caspase 9, followed by caspase 3 protease activity. Disruption of the intrinsic cell death pathway at multiple junctures led to a significant inhibition of cardiomyocyte hypertrophy during agonist stimulation, with a corresponding reduction in the expression of known hypertrophic markers (atrial natriuretic peptide) and transcription factor activity [myocyte enhancer factor-2, nuclear factor kappa B (NF-κB)]. Similarly, in vivo attenuation of caspase activity via adenoviral expression of the biologic effector caspase inhibitor p35 blunted cardiomyocyte hypertrophy in response to agonist stimulation. Treatment of cardiomyocytes with procaspase 3 activating compound 1, a small-molecule activator of caspase 3, resulted in a robust induction of the hypertrophy response in the absence of any agonist stimulation. These results suggest that caspase-dependent signaling is necessary and sufficient to promote cardiomyocyte hypertrophy. These results also confirm that cell death signal pathways behave as active remodeling agents in cardiomyocytes, independent of inducing an apoptosis response.
authors.affiliation: Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital, Ottawa, ON, Canada K1H 8L6.
authors.forename: Charis
authors.initials: C
authors.lastname: Putinski
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abdul-Ghani
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stiles
authors.forename: Steve
authors.initials: S
authors.lastname: Brunette
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Dick
authors.forename: Pasan
authors.initials: P
authors.lastname: Fernando
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Megeney
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006984:Hypertrophy; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D015853:Cysteine Proteinase Inhibitors; D019332:Endothelin-1; D009842:Oligopeptides; D014662:Vasoconstrictor Agents; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; D000804:Angiotensin II; D010656:Phenylephrine; D053148:Caspase 3; D053453:Caspase 9; D007545:Isoproterenol